Project Summary Cocaine use disorder is a chronic disease that takes a huge toll on society, and there is currently a lack of understanding of the cellular and circuit adaptations that take place in response to contingent drug use. While studies have examined excitatory signaling, there has been less focus on inhibitory neurotransmission in brain regions that play a central role in addictive behaviors. Elucidation of drug- induced adaptations to inhibitory neural circuits could provide a means to prevent and treat addiction. Chronic cocaine increases dopamine transporter (DAT) function and preliminary data suggests altered D2 autoreceptor inhibition, thus affecting the efficacy of the neurotransmitter dopamine (DA). However, midbrain DA neurons project to anatomically distinct brain regions that serve diverse functions. It is unclear how differentially projecting DA neurons diverge in their mechanisms of inhibitory neurotransmission or how these pathways may be altered following cocaine self-administration. Dopamine neurons communicate with each other through D2 autoreceptor-mediated inhibitory synaptic currents (D2-IPSCs). D2 autoreceptors activate G-protein gated inward rectifying potassium (GIRK) channels, an inhibitory signal, which plays a key role in regulating the pattern and rate of DA neuron firing. Our group has established that signaling at dendrodentritic DA synapses undergoes long-term depression (LTDDA), a unique form of plasticity. The effects of cocaine self-administration on D2-IPSCs are not known, or whether cocaine can induce DA plasticity in a projection-specific manner. To address these questions we will examine DA autoreceptor signaling and the effects of cocaine self- administration in mouse brain slices. We will examine DA neurons in the ventral tegmental area and substantia nigra that project to distinct areas: the nucleus accumbens (meso-accumbal), the amygdala (meso-amygdaloid) and the dorsal striatum (nigrostriatal). Our central hypothesis is that that DA neurons projecting to discrete areas will exhibit distinct functional markers of inhibitory neurotransmission (D2, GIRK, LTDDA) and that cocaine self-administration will attenuate inhibitory input to the meso-accumbal pathway to the greatest extent as a result of changes in D2 and GIRK availability as well as DAT functionality. No study to date has investigated cocaine-induced plasticity of dopamine autoreceptor-mediated inhibition in a projection-specific manner, making this study innovative. These experiments will contribute significant data that further elucidates mechanisms responsible for alterations in D2 inhibitory neurotransmission in different circuits in response to cocaine self-administration. This research can have great impact by providing a framework for discovery of targeted therapeutic agents to treat drug abuse. Finally, the proposed aims will provide excellent opportunities to expand my training such that I will successfully reach my goal to become an exceptional independent investigator in the field of drug abuse.